tbuckley/cabot-search huggingface dataset:
A novel polymeric peptide delivery platform and association with targeted co-delivery of antigens and STING agonists with antitumor immune response.
Authors: Max Mu Wang, Mi Ran Choi, Bin Zhang, Nathan Gianneschi
Journal: Journal of Clinical Oncology (2022)

2564 Background: Use of tumor antigens for the development of patient-specific cancer vaccines has been a promising therapeutic strategy. However, challenges remain in delivering subunit vaccine components in a coordinated fashion to elicit antitumor immune responses. To overcome these, we developed rationally designed vaccines using a novel nanoplatform called the Protein-Like Polymer (PLP), in reference to its globular structure reminiscent of native proteins, with unique characteristics that allow for sustained/targeted delivery of tumor antigens in conjunction with STING agonists. Methods: PLPs containing a model melanoma antigen were synthesized via ring-opening metathesis polymerization (ROMP) and characterized. A library of compounds were generated with different sidechain linkage chemistries (amide, ester, or disulfide), degrees of polymerization, and inclusion/exclusion of Oligo(ethylene glycol) (OEG) side chains. In vitro uptake and functional assays using gp100-specific T Cells were conducted with fluorescently-labeled and non-labeled polymers respectively. In vivo experiments were done using a B16F10 murine melanoma tumor model over-expressing gp100. Ability of PLPs to co-deliver immunomodulatory compounds was tested by electrostatically coupling a small molecule STING agonist 2’3’ cGAMP which formed stable nanostructures. The optimized construct was also tested in an OVA system to prove generalizability. Results: Conjugating peptide antigens using a cleavable disulfide linkage, which reduces intracellularly in antigen presenting cells (APCs), resulted in increased endosomal localization and efficacy. Incorporating a diluent amount of OEG side chains increased resistance to enzymatic degradation while improving bioactivity and uptake by APCs. In vivo studies using PLPs conjugated with gp100 resulted in significant increases in survival time and reduced tumor burden in B16 melanoma. Increasing the DP, and therefore the density of antigen side chains, improved vaccine efficacy and resistance to proteolysis. Mice treated with STING-PLP complexes showed significantly smaller tumors vs control at day 14 (0.038g vs 0.76g; p &lt; 0.0001) and allowed for subcutaneous administration of 2’3’ cGAMP, which otherwise diffuses rapidly away from the injection site. OVA-PLPs behaved similarly in their cognate system but showed no activity when tested on gp100-specific cells and vice versa demonstrating antigen-specificity. Conclusions: This work validates the potential of PLPs to overcome major limitations in cancer vaccine development. The modularity of the platform allows for complex nano-architectures including systems capable of delivering challenging compounds, ie small molecule STING agonists, subcutaneously through electrostatic coupling. This technology has the potential to revolutionize cancer vaccinology.
Survival of elderly patients with HER2+/HR- metastatic breast cancer in clinical practice: SEER-Medicare data 2012-2016.
Authors: Zhonghui Ou, Laura Spring, Anju Nohria, John D. Seeger, Irene Murimi-Worstell
Journal: Journal of Clinical Oncology (2022)

1039 Background: Older patients with human epidermal growth factor 2-positive (HER2+) metastatic breast cancer(mBC) are underrepresented in clinical trials. We aim to assess the overall survival (OS) and breast cancer-specific survival of elderly women with de novo HER2+/hormone receptor-negative (HR-) mBC in a real-world setting. Methods: Elderly women with HER2+/HR- mBC treated with chemotherapy and/or HER2-targeted agents and with continuous Medicare Part A, B, and D coverage 1-year before diagnosis were identified from the SEER-MEDICARE database 2012-2016. Patients were retrospectively followed from metastatic diagnosis until death, disenrollment from Medicare A, B, or D, or end of the observation period. Patients' year and month of diagnosis and death were retrieved from SEER. Death dates were verified with Medicare records reported by the Social Security Administration (SSA). For all-cause deaths, Kaplan-Meier analysis was used to estimate overall survival. The cumulative incidence competing risk (CICR) method based on cumulative incidence function (CIF) was used to estimate breast cancer-specific death incidence. Results: Seventy-three patients (mean age at diagnosis, 75.0±7.7 years) met the inclusion criteria. Among them, 56 were treated with trastuzumab ± pertuzumab /chemotherapy as first-line treatment, and 17 were treated with chemotherapy only. The median time to initiate trastuzumab-based treatment from diagnosis was 2.5 months, and the longest trastuzumab treatment length was over 44 months. The median follow-up for OS was 13 months. One patient developed stomach cancer 6 months after breast cancer diagnosis. In Kaplan-Meier analysis, censoring or not censoring this patient after second cancer development resulted in a median OS of 19 months (95% CI, 9-24 months) and 18 months (95% CI, 9-22 months). The OS at the end of 46 months was approximately 25%. Five patients died from other causes, including lung cancer, cerebrovascular diseases, aortic aneurysm and dissection, pneumonia and influenza, and heart diseases during treatment. Considering these competing risks, 50% (95% CI, 36%-64%) of patients specifically died from breast cancer between 21 and 22 months, estimated by the CICR method. Conclusions: Our study observed a shorter OS among HER2+/HR- mBC elderly patients in clinical practice than the OS of 40.8 and 56.5 months among younger patients in the CLEOPATRA trial, suggesting that age is an important prognostic factor for breast cancer survival. The presence of second cancer and other competing risks led to overestimating the probabilities of breast cancer-specific death and resulted in a shorter OS using the Kaplan-Meier method. The CICR method is more relevant to estimate the breast-cancer-specific death incidence.
Contributions of screening, early-stage treatment, and metastatic treatment to breast cancer mortality reduction by molecular subtype in U.S. women, 2000-2017.
Authors: Jennifer Lee Caswell-Jin, Liyang Sun, Diego Munoz, Ying Lu, Yisheng Li, Hui Huang, John M. Hampton, Juhee Song, Jinani Jayasekera, Clyde Schechter, Oguzhan Alagoz, Natasha K. Stout, Amy Trentham-Dietz, Jeanne S. Mandelblatt, Donald A. Berry, Sandra J. Lee, Xuelin Huang, Allison W. Kurian, Sylvia Plevritis
Journal: Journal of Clinical Oncology (2022)

1008 Background: Treatment for metastatic breast cancer has advanced since 2000, but we do not know if those advances have reduced mortality in the general population. Methods: Four Cancer Intervention and Surveillance Network (CISNET) models simulated US breast cancer mortality from 2000 to 2017 using national data on mammography use and performance, efficacy and dissemination of estrogen receptor (ER) and HER2-specific treatments of early-stage (stages I-III) and metastatic (stage IV or distant recurrence) disease, and competing mortality. Models compared overall and ER/HER2-specific breast cancer mortality rates from 2000 to 2017 relative to estimated rates with no screening or treatment, and attributed mortality reductions to screening, early-stage or metastatic treatment. Results of an exemplar model are shown. Results: The mortality reduction attributable to early-stage treatment increased from 35.8% in 2000 to 48.2% in 2017, while the proportion attributable to metastatic treatment decreased slightly from 23.9% to 20.6%. The increasing contribution of early-stage treatment reflects the transition of effective metastatic treatments to early-stage disease: accordingly, ten-year distant recurrence-free survival improved (82.5% in 2000, 87.3% in 2017; for ER+HER2+, 78.2% to 90.9%). Survival time after metastatic diagnosis also increased, doubling from 1.48 years in 2000 to 2.80 years in 2017, with the best survival for women with ER+HER2+ cancers (4.08 years) and worst for ER-HER2- (1.22 years). Conclusions: Advances in metastatic breast cancer treatment are reflected in lower population mortality, both through transition to early-stage treatment and gains for women with metastatic disease. These results may inform patient/physician discussions about breast cancer prognosis and expected benefits of treatment. [Table: see text]
Tracheitis Diagnosed With 68Ga-PSMA PET/CT in a Patient With COVID-19
Authors: Ayşegül Aksu, Kübra Bozkurt, Burçak Yılmaz
Journal: Clinical Nuclear Medicine (2022)

Abstract A 57-year-old man with newly diagnosed with prostate cancer was admitted to our department for 68 Ga–prostate-specific membrane antigen PET/CT imaging. The patient, who was asymptomatic at the time of imaging, had increased diffuse 68 Ga–prostate-specific membrane antigen uptake in the trachea on PET/CT. No ground-glass density suggestive of pneumonia in both lungs was observed. The patient, whose symptoms developed 2 days after PET/CT imaging, was diagnosed with coronavirus disease 2019 by real-time polymerase chain reaction.
GCT-18. Endoscopic third ventriculostomy (ETV) and tumor biopsy are not associated with relapse rate or patterns in primary central nervous system (CNS) germ cell tumor (GCT)
Authors: Rachel Yan, Tong Lin, Shannon MacDonald, Joseph Carnevale, Aashim Bhatia, Dennis Shaw, Erin Murphy, Sarah Leary, Ute Bartels, Soumen Khatua, Maryam Fouladi, Amar Gajjar, Girish Dhall, Jason Fangusaro, Arzu Onar-Thomas, Mark Souweidane
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: ETV and tumor biopsy are central to the surgical management of children with primary CNS GCT. An ETV creates a communication between the intraventricular compartment and the subarachnoid spaces and decompartmentalizes the ventricular system. “Tumor spill” or shedding may result from surgical interventions, such as biopsy. ETV with simultaneous biopsy may impart a greater tendency for dissemination and possible distant relapse. This is a concern in CNS GCT given the attempts of irradiation field and dose reduction following chemotherapy. METHODS: We performed a retrospective review of the prospective database for the Children’s Oncology Group (COG) ACNS1123 study. Possible associations were explored among ETV, endoscopic biopsy, and combined ETV+biopsy with relapse, distant relapse, progression free survival (PFS), and time to distant relapse. RESULTS: Among 244 eligible patients, 97 ETV+/-biopsies were performed, and 30 relapses occurred. There were no associations among ETV and/or biopsy with relapse (Cochran-Mantel-Haenszel [CMH] test, with histology (germinoma vs. nongerminomatous germ cell tumor (NGGCT)) as stratification variable: ETV: p=0.3167, biopsy: p=0.3375, combined: p=0.3066), distant relapse (CMH test, ETV: p=0.4631, ETV+biopsy: p=0.6795), PFS (log-rank test, ETV: NGGCT p=0.1632, germinoma p=0.9288; biopsy: NGGCT p=0.1682, germinoma p=0.9701; ETV+Biopsy: NGGCT p=0.1306, germinoma p=0.7758), or time to distant relapse with death/local relapse as competing risk (Gray’s test, ETV: NGGCT p=0.5694, germinoma p=0.2327; biopsy: NGGCT p=0.3505, germinoma p=0.5747; ETV+Biopsy: NGGCT p=0.3988, germinoma p=0.6839). CONCLUSIONS: Based on a secondary analysis of prospective data from the ACNS1123 trial, ETV and biopsy did not impart a greater likelihood of relapse in children with primary CNS GCT treated with combined chemotherapy and irradiation. However, three tract recurrences did occur (all germinoma), suggesting that they may affect pattern of relapse. Current and future prospective trials should continue to explore associations among these variables and relapse, including patterns of relapse.
Effect of participation in the EGFR resisters research summit on competence, performance, and professional productivity of young researchers.
Authors: Joan B. Fowler, Jill E. Feldman, Lecia V. Sequist, Rebecca Weaver, Tina Trieu, Ivy Beth Elkins
Journal: Journal of Clinical Oncology (2022)

e23010 Background: Recognizing the growing need to support early-career scientists, the EGFR Resisters Research Summit (EGFRRS) strives to identify, cultivate, and prepare young investigators (YIs) for successful careers that advance the field of EGFRm NSCLC. Methods: After a modified-NIH selection process based on submitted abstracts, a selected group of YIs were invited to the multi-day EGFRRS annually from 2019-2021. Each invitee received professional coaching, mentoring, and feedback from senior investigators and patient advocates. Changes in YI competence and performance were measured by self-assessment survey of confidence and professional productivity and analysis of abstract scores before and after receiving mentoring and coaching. Statistical testing was conducted via paired t-tests with a priori significance set at 0.05. Results: The EGFFRS included 52 unique YIs from 2019-2021, 50% female, with 44 (85%) MD/MD-PhD and 8 (15%) PhD researchers. 35 (67%) were fellows/residents and 17 (33%) were junior faculty. The mean abstract score (using a modified NIH score of 1-5 with 1 being best) improved from 2.34 prior to 2.09 post (11% improvement; P &lt; 0.005). The mean confidence score (confidence in presenting to peers; 1-4 with 4 being best) improved from 2.7 prior to 3.29 post (22% improvement; P &lt; 0.005). A follow-up survey sent to all YIs had a 46% response rate and notable findings among respondents include: 92% are still strongly or somewhat involved with EGFR lung cancer research, 96% have incorporated the patient perspective into clinical trials, 38% have collaborated with other EGFRRS participants, 46% have presented EGFR-related data at professional meetings (compared to 17% pre-EGFRRS), 25% have published EGFR-related data (compared to 10% pre-EGFRRS), 17% have obtained major grant funding (compared to 10% pre-EGFRRS), 63% remain connected to EGFRRS faculty mentors, 33% remain involved with EGFR Resisters or other patient advocacy groups. In addition, 63% report increased confidence in grant writing, 96% report increased confidence in public presentation and 100% would encourage colleagues to participate in EGFRRS. Conclusions: A research forum designed for early-career investigators can improve the performance and confidence of YIs, as well as professional productivity that is essential to their career path. These findings highlight the robust, multifaceted impact of the EGFRRS on advancing the professional development of the next generation of lung cancer researchers studying driver mutations and targeted therapies, particularly with the novel inclusion of research patient advocates to provide essential perspective.
Association of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-β and Regional Tau Burden Among Framingham Heart Study Participants Without Dementia
Authors: Leroy L. Cooper, Adrienne O’Donnell, Alexa S. Beiser, Emma G. Thibault, Justin S. Sanchez, Emelia J. Benjamin, Naomi M. Hamburg, Ramachandran S. Vasan, Martin G. Larson, Keith A. Johnson, Gary F. Mitchell, Sudha Seshadri
Journal: JAMA Neurology (2022)

Aortic stiffness is associated with clinical hallmarks of Alzheimer disease and related dementias and could be a modifiable target for disease prevention.To assess associations of aortic stiffness and pressure pulsatility with global amyloid-β plaques and regional tau burden in the brain of middle-aged and older adults without dementia.The sample for this cross-sectional study was drawn from the Framingham Heart Study Third Generation Cohort at examination 3 (N = 3171; 2016-2019), of whom 3092 successfully underwent comprehensive hemodynamic evaluations. In a supplemental visit (2015-2021), a subset of 270 participants without dementia who represented the spectrum of vascular risk also underwent positron emission tomography. Thirteen participants were excluded for missing covariate data. The final sample size was 257 participants.Three measures of aortic stiffness and pressure pulsatility (carotid-femoral pulse wave velocity, central pulse pressure [CPP], and forward wave amplitude [FWA]) were evaluated using arterial tonometry.Global amyloid-β plaques and regional tau were assessed using 11C-Pittsburgh compound B and 18F-flortaucipir positron emission tomography tracers, respectively.The mean (SD) age of the 257 participants was 54 (8) years, and 126 were women (49%). All participants were White Western European race. In multivariable models, higher CPP (β per SD = 0.17; 95% CI, 0.00-0.35; P = .045) and FWA (β per SD = 0.16; 95% CI, 0.00-0.31; P = .04) were associated with greater entorhinal tau burden. In similar models, higher CPP (β per SD = 0.19; 95% CI, 0.02-0.36; P = .03) and FWA (β per SD = 0.17; 95% CI, 0.01-0.32; P = .03) were associated with greater rhinal tau burden. Aortic stiffness and pressure pulsatility measures were not associated with amygdala, inferior temporal, precuneus tau burden, or global amyloid-β plaques. Associations for entorhinal and rhinal tau outcomes were more prominent in older participants (≥60 years). For example, higher levels of all aortic stiffness and pressure pulsatility measures (β per SD = 0.40-0.92; P = .001-.02) were associated with higher entorhinal tau burden among older but not younger participants in stratified analyses.In this cross-sectional study, abnormal central vascular hemodynamics were associated with higher tau burden in specific brain regions. Findings suggest that aortic stiffness, which is potentially modifiable, may be a probable independent target for prevention of tau-related pathologies.
COVID-19 Vaccination During Pregnancy—Multiple Pregnancies Need More Focus
Authors: Yakun Liu, Wenjun Tu, Yajun Chen
Journal: JAMA Pediatrics (2022)

Inbal Goldshtein, PhD; David M. Steinberg, PhD; Jacob Kuint, MD; Gabriel Chodick, PhD; Yaakov Segal, MD; Shirley Shapiro Ben David, MD; Amir Ben-Tov, MD
PLAG1 dampens protein synthesis to promote human hematopoietic stem cell self-renewal
Authors: Ava Keyvani Chahi, Muluken S. Belew, Joshua Xu, He Tian Tony Chen, Stefan Rentas, Veronique Voisin, Gabriela Krivdova, Eric Lechman, Sajid A. Marhon, Daniel D. De Carvalho, John E. Dick, Gary D. Bader, Kristin J. Hope
Journal: Blood (2022)

Abstract Hematopoietic stem cell (HSC) dormancy is understood as supportive of HSC function and its long-term integrity. Although regulation of stress responses incurred as a result of HSC activation is recognized as important in maintaining stem cell function, little is understood of the preventive machinery present in human HSCs that may serve to resist their activation and promote HSC self-renewal. We demonstrate that the transcription factor PLAG1 is essential for long-term HSC function and, when overexpressed, endows a 15.6-fold enhancement in the frequency of functional HSCs in stimulatory conditions. Genome-wide measures of chromatin occupancy and PLAG1-directed gene expression changes combined with functional measures reveal that PLAG1 dampens protein synthesis, restrains cell growth and division, and enhances survival, with the primitive cell advantages it imparts being attenuated by addition of the potent translation activator, c-MYC. We find PLAG1 capitalizes on multiple regulatory factors to ensure protective diminished protein synthesis including 4EBP1 and translation-targeting miR-127 and does so independently of stress response signaling. Overall, our study identifies PLAG1 as an enforcer of human HSC dormancy and self-renewal through its highly context-specific regulation of protein biosynthesis and classifies PLAG1 among a rare set of bona fide regulators of messenger RNA translation in these cells. Our findings showcase the importance of regulated translation control underlying human HSC physiology, its dysregulation under activating demands, and the potential if its targeting for therapeutic benefit.
Feasibility of disease recurrence monitoring in liver post-transplantation for patients with hepatocellular carcinoma via personalized and tumor-informed ctDNA test.
Authors: Maen Abdelrahim, Abdullah Esmail, Ashish Saharia, Robert McMillan, Aiwu Ruth He, Jason S. Starr, Harmeet Dhani, Vasily N. Aushev, Allyson Koyen Malashevich, Nicole Hook Rattigan, Phil Gauthier, Adham Jarudi, Rafik Mark Ghobrial
Journal: Journal of Clinical Oncology (2022)

e16123 Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy for which liver transplantation can be curative. Unfortunately, ̃8-20% of HCC patients will go on to relapse post-transplantation. Personalized and tumor-informed circulating tumor DNA (ctDNA) testing (Signatera, bespoke mPCR NGS assay) has been validated to accurately predict relapse across solid tumors, ahead of radiological imaging. Here, we demonstrate the feasibility of ctDNA testing for monitoring relapse in HCC patients who underwent liver transplantation with curative intent. Methods: A total of 10 HCC patients, stage I-IV, who underwent curative liver transplantation with longitudinal ctDNA monitoring were included in the analysis. Alpha-fetoprotein (AFP) levels and images were measured during surveillance in a subset of patients. Results: In this cohort of 10 patients, 2 (20%) tested ctDNA positive during surveillance, both of whom relapsed. Of these, one tested ctDNA positive two months prior to imaging. Of the 8 patients who did not test ctDNA positive during surveillance, all remained disease-free by imaging. Two patients had elevated AFP, neither of whom relapsed. Of the 2 patients who relapsed, AFP levels were available for one patient and fell within the normal range. Conclusions: Our study illustrated the feasibility of performing longitudinal ctDNA assessment in patients with HCC (post-transplantation) during surveillance. ctDNA status but not AFP was associated with recurrence and was able to inform disease status ahead of imaging. To facilitate clinical decision-making, specifically with adjuvant therapy and immunosuppression management, additional studies with larger patient cohorts will be needed to validate the clinical utility of ctDNA testing in HCC.